ABSTRACT Human infection by the spirochete Borrelia miyamotoi is a newly-recognized public health threat in the US and other parts of the world. Borrelia miyamotoi infection may require hospitalization, with symptoms that include high fever, joint and muscle pain, and meningoencephalitis. B. miyamotoi is spread by the bites of infected Ixodes spp. ticks, but almost nothing is known about how or where the bacterium colonizes its vector, or the dynamics of transmission. This proposal brings together an expert team of Borrelia and tick researchers, who will conduct a series of synergistic studies that will greatly expand understanding of B. miyamotoi transmission and infection mechanisms.